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Due to its peculiar and highly variable nature, the blazar 3C 454.3 has been extensively monitored by the WEBT team. Here, we present for the first time these long-term optical flux and color variability results using data acquired in B , V , R , and I bands over a time span of about two decades. We include data from WEBT collaborators and public archives such as SMARTS, Steward Observatory, and Zwicky Transient Facility. The data are binned and segmented to study the source over this long term when more regular sampling was available. During our study, the long-term spectral variability reveals a redder-when-brighter trend, which, however, stabilizes at a particular brightness cutoff of ∼14.5 mag in the I band, after which it saturates and evolves into a complex state. This trend indicates increasing dominance of jet emission over accretion disk (AD) emission until jet emission completely dominates. Plots of the variation in spectral index (following F _ν ∝ ν ^− ^α ) reveal a bimodal distribution using a one-day binning. These correlate with two extreme phases of 3C 454.3, an outburst or high-flux state and a quiescent or low-flux state, which are respectively jet- and AD-dominated. We have also conducted intraday variability studies of nine light curves and found that six of them are variable. Discrete correlation function analysis between different pairs of optical wave bands peaks at zero lags, indicating cospatial emission in different optical bands.

We study the broadband emission of Mrk 501 using multiwavelength observations from 2017 to 2020 performed with a multitude of instruments, involving, among others, MAGIC, Fermi's Large Area Telescope (LAT), NuSTAR, Swift, GASP-WEBT, and the Owens Valley Radio Observatory. Mrk 501 showed an extremely low broadband activity, which may help to unravel its baseline emission. Nonetheless, significant flux variations are detected at all wave bands, with the highest occurring at X-rays and very-high-energy (VHE) γ -rays. A significant correlation (>3 σ ) between X-rays and VHE γ -rays is measured, supporting leptonic scenarios to explain the variable parts of the emission, also during low activity. This is further supported when we extend our data from 2008 to 2020, and identify, for the first time, significant correlations between the Swift X-Ray Telescope and Fermi-LAT. We additionally find correlations between high-energy γ -rays and radio, with the radio lagging by more than 100 days, placing the γ -ray emission zone upstream of the radio-bright regions in the jet. Furthermore, Mrk 501 showed a historically low activity in X-rays and VHE γ -rays from mid-2017 to mid-2019 with a stable VHE flux (>0.2 TeV) of 5% the emission of the Crab Nebula. The broadband spectral energy distribution (SED) of this 2 yr long low state, the potential baseline emission of Mrk 501, can be characterized with one-zone leptonic models, and with (lepto)-hadronic models fulfilling neutrino flux constraints from IceCube. We explore the time evolution of the SED toward the low state, revealing that the stable baseline emission may be ascribed to a standing shock, and the variable emission to an additional expanding or traveling shock.

Background: Dietary high salt (HS) intake has a strong impact on cardiovascular diseases. Here, we investigated the link between HS-aggravated immune responses and the development of hypertensive vascular disease., Methods: ApolipoproteinE-deficient mice were transiently treated with HS (1% NaCl) via drinking water for 2 weeks, followed by a washout period, and subsequent Ang II (angiotensin II) infusion (1000 ng/kg per min for 10 days) to induce abdominal aortic aneurysms/dissections and inflammation., Results: While transient HS intake alone triggered nonpathologic infiltration of activated T cells into the aorta, subsequent Ang II infusion increased mortality and the incidence of abdominal aortic aneurysms/dissections and atherosclerosis compared with hypertensive control mice. There were no differences in blood pressure between both groups. In transient HS-treated hypertensive mice, the aortic injury was associated with increased inflammation, accumulation of neutrophils, monocytes, CD69 + CD4 + T cells, as well as CD4 + and CD8 + memory T cells. Mechanistically, transient HS intake increased expression levels of aortic RORγt as well as splenic CD4 + T H 17 and CD8 + T C 1 T cells in Ang II-treated mice. Isolated aortas of untreated mice were incubated with supernatants of T H 17, T H 1, or T C 1 cells polarized in vitro under HS or normal conditions which revealed that secreted factors of HS-differentiated T H 17 and T C 1 cells, but not T H 1 cells accelerated endothelial dysfunction., Conclusions: Our data suggest that transient HS intake induces a subclinical T-cell-mediated aortic immune response, which is enhanced by Ang II. We propose a 2-hit model, in which HS acts as a predisposing factor to enhance hypertension-induced T H 17 and T C 1 polarization and aortic disease., Competing Interests: None.

Targeting AML by chimeric antigen receptor T-cells (CAR-T) is challenging due to the promiscuous expression of AML-associated antigens in healthy hematopoiesis and high degree of inter- and intratumoral heterogeneity. Here, we present single-cell expression data of AML-associated antigens in 30 primary pediatric AML samples. We identified CD33, CD38, CD371, IL1RAP and CD123 as the most frequently expressed. Notably, high variability was observed not only across the different patient samples but also among leukemic cells of the same patient suggesting the necessity of multiplexed targeting approaches. To address this need, we utilized our modular Adapter CAR (AdCAR) platform, enabling precise qualitative and quantitative control over CAR-T-cell function. We show highly efficient and target-specific activity for newly generated adapter molecules (AMs) against CD33, CD38, CD123, CD135 and CD371, both in vitro and in vivo. We reveal that inherent intratumoral heterogeneity in antigen expression translates into antigen escape and therapy failure to monotargeted CAR-T therapy. Further, we demonstrate in PDX models that rational combinatorial targeting by AdCAR-T-cells can cure heterogenic disease. In conclusion, we elucidate the clinical relevance of heterogeneity in antigen expression in pediatric AML and present a novel concept for precision immunotherapy by combinatorial targeting utilizing the AdCAR platform., (© 2024. The Author(s).)

Aim: To investigate the professional dementia experts' understanding of a dementia-friendly hospital to identify its characteristics., Design: We used a qualitative design embedded in a case study. A total of 16 semi-structured expert interviews were conducted with 17 professional dementia experts. Using inductive content analysis, the interviews were analysed in a participatory manner involving a group of researchers and dementia experts., Results: We identified six characteristics of dementia-friendly hospitals: Proud to be dementia-friendly-That's what we want; Seeing the human being-Taking care of everyone; Having everyone on board-It's a collective task; Being professional-It takes more than being nice and kind; Rethinking the 'running' system-We have to change, not them; and Being part of the community-Thinking beyond the hospital., Conclusion: The concept of a dementia-friendly hospital seems complex and requires a rethinking of the traditional hospital. For a conceptualisation, the involvement of people with dementia and their relatives is important to gain a comprehensive understanding., Implications for the Profession and Patient Care: A dementia-friendly hospital is characterised by professional care that comprises a safe, familiar and supportive environment, is prepared but also flexible, has everyone on board, and sees the human being. To become dementia-friendly, individual interventions such as training courses can be a starting point. However, an overall concept is required that also includes components that contribute to successful implementation and a welcoming culture of people with dementia., Impact: Our findings on the perspective of professional dementia experts contribute to the conceptualisation of dementia-friendly hospitals., Reporting Method: We reported our study according to the COREQ checklist., Patient and Public Contribution: The investigation of the perspective of professional dementia experts is one part of a larger study. In this overall DEMfriendlyHospital study, we interviewed professional dementia experts, people with dementia and their relatives and also involved them in a participatory manner in various stages of the research process., (© 2024 The Author(s). Journal of Clinical Nursing published by John Wiley & Sons Ltd.)

Recruiting the endogenous editing enzyme adenosine deaminase acting on RNA (ADAR) with tailored guide RNAs for adenosine-to-inosine (A-to-I) RNA base editing is promising for safely manipulating genetic information at the RNA level. However, the precision and efficiency of editing are often compromised by bystander off-target editing. Here, we find that in 5'-UAN triplets, which dominate bystander editing, G•U wobble base pairs effectively mitigate off-target events while maintaining high on-target efficiency. This strategy is universally applicable to existing A-to-I RNA base-editing systems and complements other suppression methods such as G•A mismatches and uridine (U) depletion. Combining wobble base pairing with a circularized format of the CLUSTER approach achieves highly precise and efficient editing (up to 87%) of a disease-relevant mutation in the Mecp2 transcript in cell culture. Virus-mediated delivery of the guide RNA alone realizes functional MeCP2 protein restoration in the central nervous system of a murine Rett syndrome model with editing yields of up to 19% and excellent bystander control in vivo., (© 2024. The Author(s).)

Background: An abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease. Although its pathogenesis is still poorly understood, recent evidence suggests that AAA displays autoimmune disease characteristics. Particularly, T cells responding to AAA-related antigens in the aortic wall may contribute to an initial immune response. Single-cell RNA (scRNA) T cell receptor (TCR) and B cell receptor (BCR) sequencing is a powerful tool for investigating clonality. However, difficulties such as limited numbers of isolated cells must be considered during implementation and data analysis, making biological interpretation challenging. Here, we perform a representative single-cell immune repertoire analysis in experimental murine AAA and show a reliable bioinformatic processing pipeline highlighting opportunities and limitations of this approach., Methods: We performed scRNA TCR and BCR sequencing of isolated lymphocytes from the infrarenal aorta of male C57BL/6J mice 3, 7, 14, and 28 days after AAA induction via elastase perfusion of the aorta. Sham-operated mice at days 3 and 28 and non-operated mice served as controls., Results: Comparison of complementarity-determining region (CDR3) length distribution of 179 B cells and 796 T cells revealed neither differences between AAA and control nor between the disease stages. We found no clonal expansion of B cells in AAA. For T cells, we identified several clones in 11 of 16 AAA samples and one of eight control samples. Immune receptor repertoire comparison indicated that only a few clones were shared between the individual AAA samples. The most frequently used V-genes in the TCR beta chain in AAA were TRBV3, TRBV19, and the splicing variant TRBV12-2 + TRBV13-2., Conclusion: We found no clonal expansion of B cells but evidence for clonal expansion of T cells in elastase-induced AAA in mice. Our findings imply that a more precise characterization of TCR and BCR distribution requires a more extensive number of lymphocytes to prevent undersampling and potentially detect rare clones. Thus, further experiments are necessary to confirm our findings. In summary, this paper examines TCR and BCR sequencing results, identifies limitations and pitfalls, and offers guidance for future studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Elster, Ommer-Bläsius, Lang, Vajen, Pfeiler, Feige, Yau Pang, Böttenberg, Verheyen, Lê Quý, Chernigovskaya, Kelm, Winkels, Schmidt, Greiff and Gerdes.)

Background: To become a dementia-friendly hospital (DFH) is increasingly being discussed in health care practice, research, politics and society. In our previous integrative review, we identified six characteristics of DFHs. To thoroughly discuss and contextualize these characteristics in relation to hospitals in Germany, we involved professional dementia experts in our review process., Methods: At the end of our review process, we involved professional dementia experts at the 'contributing' level of the ACTIVE framework to discuss and reflect on the six DFH characteristics we identified. We conducted a group process in the form of a one-day workshop. The workshop consisted of four steps: 1. presentation of review results (input), 2. modification of DFH characteristics and rating of their relevance in smaller working groups, 3. discussion of group results in plenary and 4. questionnaire for prioritization and rating of feasibility. The data were analyzed in MAXQDA using content analysis and descriptive statistics., Results: A total of 16 professional dementia experts working in hospitals participated in the workshop. All the previously identified characteristics of a DFH were rated as relevant or very relevant for patients with dementia, their relatives and health care professionals from the professional dementia experts' perspective. They made a few modifications of the six characteristics at the level of subcategories, aspects, and descriptions. The feasibility of the characteristics in hospitals was critically discussed regarding resources, hospital structures and processes, the role of nurses, and the current care situation of people with dementia in hospitals. More than half of the subcategories of the characteristics were considered very difficult or difficult to implement by most professional dementia experts., Conclusion: The involvement of professional dementia experts helped us contextualize our review findings within the German hospital setting. These results highlight the need to consider resources, funding options, influencing factors, and the current situation and culture of care provided by hospitals before implementing DFH characteristics. Beside the involvement of professional dementia experts and various health care professionals, the involvement of other stakeholders, such as people with dementia and their relatives, is necessary in future research for the development of a DFH., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Human cytomegalovirus (HCMV) is a herpesvirus that causes life-threatening infections in newborns or immunosuppressed patients. For viral replication, HCMV establishes a network of cellular interactions, among others cyclin-dependent kinases (CDK). Furthermore, HCMV encodes pUL97, a viral kinase, which is a CDK-homologue. HCMV uses pUL97 in order to phosphorylate and thereby antagonize SAMHD1, an antiviral host cell factor. Since HCMV has several mechanisms to evade restriction by SAMHD1, we first analyzed the kinetics of SAMHD1-inactivation and found that phosphorylation of SAMHD1 by pUL97 occurs directly after infection of macrophages. We hence hypothesized that inhibition of this process qualifies as efficient antiviral target and FDA approved CDK-inhibitors (CDKIs) might be potent antivirals that prevent the inactivation of SAMHD1. Indeed, Abemaciclib, a 2nd generation CDKI exhibited superior IC50s against HCMV in infected macrophages and the antiviral activity largely relied on its ability to block pUL97-mediated SAMHD1-phosphorylation. Altogether, our study highlights the therapeutic potential of clinically-approved CDKIs as antivirals against HCMV, sheds light on their mode of action and establishes SAMHD1 as a valid and highly potent therapeutic target., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Human papillomaviruses (HPVs) are DNA tumor viruses that infect mucosal and cutaneous epithelial cells of more than 20 vertebrates. High-risk HPV causes about 5% of human cancers worldwide, and the viral proteins E6 and E7 promote carcinogenesis by interacting with tumor suppressors and interfering with many cellular pathways. As a consequence, they immortalize cells more efficiently in concert than individually. So far, the networks of E6 and E7 with their respective cellular targets have been studied extensively but independently. However, we hypothesized that E6 and E7 might also interact directly with each other in a novel interaction affecting HPV-related carcinogenesis. Here, we report a direct interaction between E6 and E7 proteins from carcinogenic HPV types 16 and 31. We demonstrated this interaction via cellular assays using two orthogonal methods: coimmunoprecipitation and flow cytometry-based FRET assays. Analytical ultracentrifugation of the recombinant proteins revealed that the stoichiometry of the E6/E7 complex involves two E7 molecules and two E6 molecules. In addition, fluorescence polarization showed that (I) E6 binds to E7 with a similar affinity for HPV16 and HPV31 (in the same micromolar range) and (II) that the binding interface involves the unstructured N-terminal region of E7. The direct interaction of these highly conserved papillomaviral oncoproteins may provide a new perspective for studying HPV-associated carcinogenesis and the overall viral life cycle., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)